225121-08-4

Upstream product

• 1871-76-7 diphenylacetic acid chloride 
• 225122-52-1 3-methyl-N-(2,2-diphenylacetyl)-L-phenylalanine 
• 225122-64-5 2-amino-4-[3-(methoxycarbonyl)-phenoxy]-butyronitrile 
• 114873-06-2 (S)-2-((tert-butoxycarbonyl)amino)-3-(m-tolyl)propanoic acid 
• 225122-62-3 methyl 3-(2-iodoethoxy)benzoate 
• 59516-96-0 1-Bromo-2-(3'-carbomethoxyphenoxy)ethane 
• 19438-10-9 methyl 3-hydroxybenzoate 
• 620-13-3 1-bromomethyl-3-methyl-benzene 

Relevant academic research and scientific papers

Dipeptide nitriles

N-terminal substituted dipeptide nitriles as defined are useful as inhibitors of cysteine cathepsins, e.g. cathepsins B, K, L and S, and can be used for the treatment of cysteine cathepsin dependent diseases and conditions, including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, tumors (especially tumor invasion and tumor metastasis), coronary disease, atherosclerosis (including atherosclerotic plaque rupture and destabilization). Particular dipeptide nitriles are compounds of formula I, or physiologically-acceptable and -cleavable esters or a salts thereof wherein: the symbols are as defined. In particular it has been found that by appropriate choice of groups R, R2, R3, R4, R5, X1, Y and L, the relative selectivity of the compounds as inhibitors of the various cysteine cathepsin types, e.g. cathepsins B, K, L and S may be altered, e.g. to obtain inhibitors which selectively inhibit a particular cathepsin type or combination of cathepsin types.

Identification of dipeptidyl nitriles as potent and selective inhibitors of cathepsin B through structure-based drug design

Cathepsin B is a member of the papain superfamily of cysteine proteases and has been implicated in the pathology of numerous diseases, including arthritis and cancer. As part of an effort to identify potent, reversible inhibitors of this protease, we examined a series of dipeptidyl nitriles, starting with the previously reported Cbz-Phe-NH-CH2CN (19, IC50 = 62 μM). High-resolution X-ray crystallographic data and molecular modeling were used to optimize the P1, P2, and P3 substituents of this template. Cathepsin B is unique in its class in that it contains a carboxylate recognition site in the S2′ pocket of the active site. Inhibitor potency and selectivity were enhanced by tethering a carboxylate functionality from the carbon α to the nitrile to interact with this region of the enzyme. This resulted in the identification of compound 10, a 7 nM inhibitor of cathepsin B, with excellent selectivity over other cysteine cathepsins.